Chiral Catalysts and Catalysis
The present invention relates to the field of asymmetric catalysis. More particularly, the invention relates to the field of organometallic catalysts useful for enantioselectively epoxidizing prochiral olefins.
Several advances in catalysis of asymmetric group transfer have occurred in recent years. One such advance has been the discovery by K. B. Sharpless et al. of the epoxidation of allylic alcohols which provides access to enantiomerically pure synthetic building blocks. Unfortunately, Sharpless catalysis requires the presence of a specific functional group, namely an allylic alcohol, on the olefin to be epoxidized. Naturally, this requirement severely limits the variety of olefins which can be so epoxidized.
Some success has been achieved in asymmetric catalysis of unfunctionalized olefins. For example, K. B. Sharpless reported in 1988 that certain cinchona alkaloid derivatives were effective ligands in the osmium-catalyzed asymmetric dihydroxylation of trans-stilbene and various other olefins. This method provides a practical route to certain chiral diols, although cis olefins afford poor results.
Aside from the catalysts disclosed herein, it is believed that there currently exists no practical catalytic method for the asymmetric epoxidation of unfunctionalized olefins. Some progress has been made in this area through the use of chiral porphyrin complexes. In particular, J. T. Groves et al. reported in 1983 the asymmetric epoxidation of styrene by a chiral iron porphyrin catalyst. Unfortunately, the Groves system suffers several disadvantages, namely, the porphyrin catalyst is relatively difficult to prepare, oxidant proceeds to low substrate conversion, is limited to styrene derivatives, and achieves enantiomeric excess (ee) values of less than about 50 percent.
Epoxychroman Synthesis
Given the broad synthetic utility of epoxides, a simple, reliable, and practical procedure for asymmetric epoxidation of simple olefins is clearly desirable. One class of chiral epoxide with synthetic utility is the group of compounds generally known as epoxychromans, or epoxides of derivatives of chromene. For example, the epoxide of 6-cyano-2,2-dimethylchromene has been found to be useful in the synthesis of a compound known as cromakalim. Two variations of cromakalim are shown in FIGS. 12 and 13. Both of these are believed to be potassium channel activators and have shown considerable promise as antihypertensive drags.
As can be seen in FIGS. 12 and 13, the cromakalim compounds have two enantiomers. It is currently believed that only one of these enantiomers, namely the 3S, 4R enantiomer, possesses the antihypertensive activity. Consequently, a method of making a more enantiomerically pure epoxide of the precursor chromene derivative is highly desirable.
Taxol Synthesis
Taxol has emerged as a promising anti-cancer drug in preliminary clinical trials. However, taxol is a highly complex molecule which has not been fully synthesized and remains in short supply. Taxol may be considered to have two basic structural units, an N-benzoyl-3-phenyl-isoserine side chain and a highly functionalized diterpene nucleus. The tetracyclic ring structure of the nucleus represents by far the greater synthetic challenge, one that has as yet not been met despite the concerted efforts of several leading laboratories.
Consequently, a number of research groups are seeking semisynthetic routes of making taxol or analogs with taxol-like activity. Some of the new strategies involve side-chain synthesis and linkage to a naturally derived diterpene nucleus, or taxol congener.
A ready source of the taxol congener 10-deacetyl baccatin III (10-DB III) has been found. Chauviere, G., Guenard, D.; Picot, F.; Senilh, V.; Potier, P. C. R.: Seances Acad. Sci., Ser. 2, 293: 501-03, 1981. Denis et al. (J. Amer. Chem. Soc. 110:5417, 1988) developed a method of converting 10-DB III to taxol which utilizes, for the taxol C13 side chain, the protected form (2R, 3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Denis, J.-N.; Greene, A. E.; Serra, A. A.; Luche, M.-J.J. Org. Chem. 51: 46-50, 1986.
A more efficient method of synthesizing an optically pure C13 side chain of taxol is desirable.
Chiral Catalysts and Oxidation of Sulfides
The present invention also relates to the field of organometallic catalysts useful for enantioselectively oxidizing sulfides to sulfoxides. Given the broad synthetic utility of surf oxides, a simple, reliable, and: practical procedure for asymmetric oxidation of sulfides is clearly desirable.
Asymmetric sulfide oxidation and olefin epoxidation strategies utilizing chiral oxaziridine derivatives have been developed with good to excellent success by Davis et al. Enantioselective catalysis of these reactions (and of asymmetric stoichiometric epoxidation)constitutes among the most interesting challenges in modem synthetic chemistry. To date, the only well-established and broadly successful methods for both these processes employ closely related Ti-tartrate-based catalysts with alkyl hydroperoxides as the terminal oxidant. Also, several chiral porphyrin complexes have been reported to catalyze both types of oxidation processes with modest selectivity using iodosylarenes as terminal oxidants.
Catalytic Disproportionation of Hydrogen Peroxide
The enzyme catalase, which occurs in blood and a variety of tissues decomposes hydrogen peroxide into oxygen gas and water very rapidly. This catalytic disproportionation of hydrogen peroxide (also known as the catalytic reaction) protects aerobic cells from oxidative stress and therefore is a biologically important process. Thus, it is desirable to find compounds which can function like catalase.